We have been following-up association signals from our prior genome-wide association (GWA) study (100k) in Pima Indians. To date, have genotyped more than 4035 SNPs for fine-mapping in several genomic regions. We are also testing the population-level significance of the best SNPs and, to date, have genotyped more than 1703 SNPs in a population-based sample of 3500 full-heritage Pima Indians. Selected SNPs are being further tested for replication in an additional 4100 Pima Indians as well as 3000 Native Americans from the Strong Heart study. We have identified variants near the NELL-1 gene that are strongly associated with diabetes and we are currently trying to establish the functional variant. In addition, we have identified variation within the A2BP1 gene that is highly associated with body mass index and we are currently trying to determine the metabolic pathway that is affected by this gene. Another SNP that was identified via the GWA mapped within the MBL2 gene that encodes the mannose-binding lectin protein. This protein is a key player in the innate immune system, and has recently been found to play a role in insulin resistance and development of type 1 diabetes and gestational diabetes. Variants which have previosuly been shown to influence serum MBL2 protein levels were associated with type 2 diabetes in two independent groups of Pima Indians as well as an Amish population.